Benzophenones-natural metabolites with great Hopes in drug discovery: structures, occurrence, bioactivities, and biosynthesis

Fungi have protruded with enormous development in the repository of drug discovery, making them some of the most attractive sources for the synthesis of bio-significant and structural novel metabolites. Benzophenones are structurally unique metabolites with phenol/carbonyl/phenol frameworks, that are separated from microbial and plant sources. They have drawn considerable interest from researchers due to their versatile building blocks and diversified bio-activities. The current work aimed to highlight the reported data on fungal benzophenones, including their structures, occurrence, and bioactivities in the period from 1963 to April 2023. Overall, 147 benzophenones derived from fungal source were listed in this work. Structure activity relationships of the benzophenones derivatives have been discussed. Also, in this review, a brief insight into their biosynthetic routes was presented. This work could shed light on the future research of benzophenones.


Research methodology
Reviewing of literature was carried out through online search on ScienceDirect, Wiley Online Library, SCOPUS, Google Scholar, PubMed, Taylor & Francis, Springer, Bentham, Thieme, and JACS. The data was retrieved using "Benzophenones + Fungi", OR "Benzophenones + Biological activity" OR "Benzophenones + Biosynthesis" as keywords. All studies that reported the isolation, structural characterization, biosynthesis, and bioactivities of fungal BPs, as well as reviews and book chapters were included. The peer-reviewed journals' English language published papers from 1963 to 2023 were included. Included studies were assessed through reading their titles, abstracts, and full texts. The no full access (e.g., conference proceedings), irrelevant, and non-reviewed journals published work were excluded. For the non-English paper, the information was extracted from the English abstracts. The reported works on BPs from other sources were not included. In the current review, a total of 110 references were discussed.

Biological activities of benzophenones
Various benzophenones derivatives have been isolated from fungi obtained from different extracts using diverse chromatographic techniques and elucidated by different spectral analyses as well as Xray, CD, ECD, and chemical methods. These metabolites have been assessed for different bioactivities that have been summarized here.

Plant growth inhibitory and anti-nematode activities
Hashimoto et al. puried and characterized compounds 3 and 4 from the EtOAc extract of Daldinia concentrica using NMR, Xray, and chemical degradation (Fig. 2). These metabolites at 5 ppm completely prohibited rice root germination in husk. 23 Also, 8 exhibited moderate (LD 90 50 ppm) anti-nematode potential versus Caenorhabditis elegans and inhibited germination of cress seeds at 100 ppm. 27

Antimicrobial, anti-mycobacterial, and antialgal activities
The microbe's resistance to the available antibiotics becomes the main health concern. Therefore, there is a pressing requirement for nding out new types of antimicrobials with unfamiliar mechanisms to overcome multidrug-resistant microbe infections. 89 Sulochrin (8) and demethylsulochrin (9) were separated from the leaf litters-derived Aspergillus species EtOAc extract by SiO 2 CC. Compound 97 had no antimicrobial capacity versus E. coli or phyto-pathogens: Rhizoctonia solani and Gaeumannomyces graminis var tritici (Conc. < 200 ppm). 27 Two new compounds: penibenzophenones A and B (17 and 18), along with 8 were isolated from the EtOAc extract of Bruguiera sexangula var. rhynchopetala-harbouring Penicillium citrinum (HL-5126) fermentation broth. Their structures were elucidated by extensive NMR, MS, and X-ray analyses (Fig. 3). Compound 17 is an example of chlorinated benzophenones. Among these metabolites, 17 revealed weak antibacterial effectiveness versus S. aureus (MIC 20 mg mL −1 ). 31 Additionally, the new benzophenone derivatives: penibenzophenones C (19) and D (20), together with 8 and 16 were separated by SiO 2 /Sephadex LH-20/HPLC from the EtOAc extract of Penicillium sp. isolated Acanthus ilicifolius collected from the South China Sea and elucidated by NMR and MS analyses. Compounds 19 and 20 demonstrated antibacterial efficacy versus MRSA (MICs 3.12 and 6.25 mg mL −1 , respectively), compared to ciprooxacin (MIC 1.56 mg mL −1 ), whilst 8 and 16 had weak activity in the microplate assay method ( Table 2). 32 Compounds 22 and 23 isolated from Aspergillus avipes DL11 were assessed for antibacterial potential against S. aureus (ATCC-43300, ATCC-29213, ATCC-33591, and ATCC-25923), E. faecalis ATCC-51299, E. faecalis ATCC-35667, and V. parahaemolyticus ATCC-17802 in the broth microdilution (Fig. 4). Interestingly, 22 revealed powerful inhibitory potential versus all S. aureus strains (MICs 1.56 to 12.5 mg mL −1 ) and moderate potential versus E. faecalis ATCC-51299 and ATCC-35667 (MICs 50 and 100 mg mL −1 , respectively). On the other hand, 23 had a potent antibacterial capacity versus all tested strains (MICs 1.56 to 12.5 mg mL −1 ) except V. parahaemolyticus ATCC-17802, compared to vancomycin HCl and ampicillin sodium. 39 Ma et al. reported the separation of rhizoctonic acid (25), a new benzophenone derivative and the formerly reported    Two new benzophenone derivatives; 37 and 38 were isolated from the EtOAc extract of Laurencia okamurai-associated Talaromyces islandicus EN-501 by SiO 2 /Sephadex LH-20 CC and HPLC and assigned by NMR and X-ray analyses (Fig. 5).

Cytotoxicity activity
Cancer is one of the most leading causes of death world-wide. In 2018, 9.6 million deaths because of cancer were stated according to WHO (World Health Organization). All over the world, it is estimated that z18.1 million cancer patients are present and this is expected to increase to 24 million in the coming decades. 91 Since the 1980s, cancer mortality has steadily increased because of various factors, including environmental conditions and dietary habits. 92 The most frequent and efficient cancer treatment strategies include chemotherapy and radiation therapy and surgical operation for early-stage cancers. 93 Unfortunately, within a few years aer cancer treatment, recurrence is observed with a rate of up to 70% according to cancer stages and types. 94 Actually, the management of recurrent cancer could be hard because of their increased aggression and metastatic capacity caused by their impedance to formerly utilized drugs. 95 BPs were tested for their cytotoxic capacity against various cancer cell lines using MTT or SRB assay. These reports were highlighted below (Table 3) (Table 3).
Xu et al. reported the separation of ve new benzophenone derivatives: tenellones D-H (73-77), sharing a rare aldehyde at C-2 and isoprenyl at C-6, together with the known metabolite 69 from marine sediment-derived Phomopsis lithocarpus FS508   (Fig. 7). 65 It was noted that metabolites with an isoprenyl group in ring A had no activity (e.g., 77 vs. 73-76 and 69) 65 (Fig. 8). Additionally, new benzophenone analogues: 78, 79, 103, and 104 were characterized from the same fungus by Liu et al. utilizing NMR, ECD, and Xray analyses. Their potential anticancer activities versus SF-268, MCF-7, HepG-2, and A549 cell lines were     66 On the other hand, 129 showed cytotoxicity towards CHO, HepG2, MRC5, and HEK293 with IC 50 9.0-25.0 mM in the MTT assay. 85 New halogenated benzophenone derivatives: pestalones B-H (81)(82)(83)(84)(85)(86)(87), in addition to 80 and 99 were obtained from the EtOAc extract of Pestalotiopsis neglecta that was cultured in fermentation media supplemented with halide salts using SiO 2 CC and RP-HPLC and dened by spectroscopic and Xray analyses (Fig. 9). Compounds 82 and 84 displayed the most powerful anti-proliferation potential versus PANC-1 cells (IC 50 s 7.6 and 7.2 mM, respectively), comparing to 5-Fu (IC 50 15.0 mM), while 85, 80, and 86/87 mixture had less potent effectiveness (IC 50 14.0 mM) than 82 and 84 but better than 81 (IC 50 26.0 mM) in the MTT assay. It was indicated that a second halogen atom and/or a methoxy in ring B substitution had no effect on the potency of these metabolites. In addition, 82 and 84 signicantly repressed the PANC-1 cells' colony formation in the colony formation assay that supported their anti-proliferation ability of PANC-1 cells via boosting the caspase-3 and PARP's cleavage resulting in PANC-1 apoptosis. 69 They possible induced their effect through prohibition of ERK/MEK pathway. 69 In the cytotoxicity assay, 68, 80, 84, and 85 with a C-14 aldehyde group exhibited cytotoxic effectiveness (IC 50 57 The red alga Grateloupia turuturu-derived Penicillium chrysogenum AD-1540 yielded two new benzophenone derivatives 95 and 96. Their structures and conguration were characterized relying on spectroscopic, coupling constants, and TDDFT calculations of ECD spectra. These metabolites are structural related to xanthones, while they featured an uncommon fused dihydropyran ring and an opened ring C. Both compounds revealed moderate to weak cytotoxic potential (IC 50 s 20.4-46.7 mM) versus BT-549, A549, HeLa, MCF-7, HepG2, and THP-1 cell lines in the CCK-8 method compared to epirubicin (IC 50 s 2.9 to 7.2 mM). 74 In 2017, Lei et al. also reported the separation of 99 from a culture of Phakellia fusca-associated Pestalotiopsis heterocornis that was assessed for cytotoxic potential versus BGC-823, H460, PC-3, and SMMC-7721 in the MTT assay (Fig. 10). This compound displayed marked activity versus BGC-823 and SMMC-7721 (IC 50 s 6.8 and 7.9 mM, respectively) compared to adriamycin (IC 50 s 1.5 and 2.2, respectively), whereas it was   76 The cytotoxicity investigation of 114-117 versus HepG-2, H460, MCF-7, and SF-268 cell lines in the SRB method revealed the weak potential of 115 and 117 (IC 50 ranged from 29.4 to 68.6 mM) versus these cell lines 82 (Fig. 11 and 12). Compounds 10, 25, and 127 were assessed for their cytotoxic potential versus HepG2 using the MTT assay. Among them, 127 was the most active (IC 50 5.2 mM) than the its related monomers 10 and 25 (IC 50 s 63.5 and 60.2 mM, respectively) in comparison to 5-Fu (IC 50 19.2 mM). 36 From the unidentied fungus MSX 17022 belonging to Hypocreales, 1, 123, and 125 were separated (Fig. 12). In the SRB assay, 123 possessed cytotoxic effectiveness versus MCF-7, H460, and SF268 (IC 50 s 18.1, 13.6, and 21.4 mM, respectively), however, 125 had noticeable activity versus H460 and SF268 (IC 50 s 20.6 and 21.0 mM, respectively). 19 In the brine shrimp lethality, 28 exhibited lethality potential (LD 50 25.3 mM), compared to colchicine (LD 50 1.22 mM). Also, 10 and 127 reported from Solanum insanum-associated Aspergillus fumigatus displayed brine shrimp toxicity (IC 50 74.2 mM) (Fig. 13). 37 In 2017, Liao et al. reported the purication of novel diastereomeric lipo-peptidyl benzophenones: asperphenins A (146) and B (147) from the MeOH extract of marine-derived Aspergillus sp. using RP-18 CC and HPLC, which were characterized based on spectroscopic, CD, and ECD analyses, as well as Mosher's method. These compounds are C-17 epimers, having R and S conguration, respectively and their structures involve trihydroxybenzophenone, 3-hydroxydodecanoic acid, and tripeptide moieties. Both 146 and 147 exhibited signicant antiproliferative activity versus RKO, SNU638, SK-HEP-1, and MDA-MB-231 cell lines (IC 50 s ranged from 0.8 to 9.7 mM) in the MTT assay. It is worth that RKO cells were the most sensitive cell lines towards 146 and 147 (IC 50 s 0.8 and 1.1 mM, respectively), compared to etoposide (IC 50 3.3 mM). 88 In 2020, Bae et al. also reported the antitumor potential of 146 and 147 versus SK-HEP-1, RKO, MAD-MB-231, and SNU638 cell lines (IC 50 s ranged 0.84-6.48 mM for 146 and 1.26-9.43 mM for 147). Further, studying the antiproliferative mechanism of 146 on RKO cells revealed that 146 suppressed RKO growth via arresting G2/M cell cycle through prohibiting microtubule polymerization with subsequent apoptosis. It also induced reactive oxygen species and repressed the tumor growth in a colon cancer xenogra model without any toxicity. Interestingly, it possessed synergistic inuence with irinotecan (topoisomerase I inhibitor), however, it had antagonistic inuence with paclitaxel that indirectly supported their opposite molecular mechanisms. It was found that the aryl ketone moiety is accountable for 146's activity. 96 Therefore, 146 could be new lead metabolite for nding out chemotherapeutic agents with antimitotic capacity.
In the same aspect, Byun et al. demonstrated that 147 possessed potent cytotoxic potential versus human CRC (colorectal cancer) cell lines: HCT-116, RKO, Ls174T, and SW480 (IC 50 s ranged from 0.93 to 47.18 mM) compared to etoposide in the SRB assay. Compound 147 was found to induce cell cycle arrest at G2/M phase and with subsequent apoptotic cell death, also, it suppressed tumor growth in a xenogra model. 95 Its G2/ M phase arrest inuence was accompanied with the check-point proteins (Cdc25c and Chk1/2) regulation, whereas its apoptosis potential was linked to survivin down-regulation and cleaved caspases and p53 upregulation. Further, it boosted the repression of HCT-116 cells invasion and migration through GAPDH (glyceraldehyde-3-phosphate dehydrogenase) downregulation. Also, it upregulated E-cadherin and down-regulated Snail and N-cadherin, conrming its antimetastatic effectiveness. Hence, its antimetastatic and antitumor potential was determined to be due to modulating GAPDH-induced EMT processes. This highlighted the potential of 147 as promising candidate for metastatic CRC treatment. 95

Antioxidant activity
Some of the reported BPs possessed potent antioxidant potential than positive controls. Herein, the reported studies on the antioxidant activity were discussed and the results were listed in Table 4.

Immune-suppressive activity
Most of the immunological disorders are resulted from immune cells' abnormally low or over activity. In immune-system overactivity, the body damages and attacks its own tissues referring to an acquired immune system reaction. Immune-suppressants are utilized to control autoimmune disorders and improved allogra survival, however, they possess deleterious side effects. 97 From the EtOAc extract of Penicillium sp. ZJ-SY2 isolated from Sonneratia apetala leaves, two new benzophenone derivatives; peniphenone (39) and methyl peniphenone (40) were separated using SiO 2 /Sephadex LH-20/RP-HPLC. Their immunosuppressive potential versus Con A-caused T cell and LPSinduced B cell proliferations of mouse splenic lymphocytes in

Anticoccidial and anti-malarial activities
Eimeria spp. causes coccidiosis, which is a signicant parasitic disease affects chickens, resulting in serious economic losses through mortality and morbidity. The anticoccidial agents such as polyether ionophore are successfully utilized in poultry industry. Unfortunately, resistance has been observed to the existing anti-coccidiosis agents, therefore, search for new therapeutic agents for coccidiosis control are needed. 98 Bioassay-guided fractionation of Diaporthe sp. associated with Aeonium cuneatum stems resulted in the purication of 69 and 70, two new highly substituted benzophenones from the methyl ethyl ketone extract using Sephadex LH-20 and HPLC, which were determined by spectroscopic and Xray analyses. They featured trioxygenated isopentane and 1,4-dioxane moieties, respectively. Their Eimeria tenella PKG (cGMP-dependentprotein kinase) and Toxoplasma gondii whole cell (TgWC) inhibition capability was estimated using radiometric and b-  64 Investigation of the insect-associated Orbiocrella petchii BCC 51377 EtOAc extract using RP-18/SiO 2 /Sephadex LH-20 CC and RP-HPLC resulted in orbiophenone A (44, benzophenone derivative), orbiocrellone A (131, homodimer of 44), orbiocrellones B-E (132-135, chromone-benzophenone heterodimers), and ent-secalonic acid I (144, tetrahydroxanthonebenzophenone dimer) that were elucidated by spectroscopic and chemical analyses, additionally their absolute conguration was established by ECD spectra and ECD-TD-DFT calculation. Compound 131 is a C-11-C-11 ′ symmetric homodimer of 44. Besides, 133 is an isomer of 132, differing in the dimerization position and 144 with 5 ′ S/6 ′ R/10a ′ S conguration is an enantiomer secalonic acid I formerly reported from Penicillium oxalicum. 99 Compounds 132, 133, 134, and 144 revealed antimalarial potential versus Plasmodium falciparum K1 (IC 50 s 5.7, 5.6, 14.0, and 5.5 mM, respectively) compared to dihydroartemisinin (IC 50 0.0025 mM) in the microculture radioisotope technique. 53

Anti-inammation activity
The new derivatives: eurobenzophenones A-C (47-49), alongside 8 and 12-15 (Conc. 10 mM) exerted inhibition potential versus NO production boosted LPS in the BV2 cells (% inhibition 17.4-39.4%), compared to curcumin (% inhibition 60%). Compound 8, 12, and 48 (Conc. 10 mM) remarkably declined NF-kB expression (inhibitory rates 67.2, 71.0, and 74.9%, respectively), compared to MIG132 (NF-kB inhibitor, 90% inhibitory rate, Conc. 10 mM). 30 The signicant inhibitory potential of 48 toward NO was mediated by NF-kB down-regulation. 30 Tenellone D (72) a new derivative along with 71 were separated from Diaporthe sp. SYSU-HQ3 CH 2 Cl 2 extract by different chromatographic methods. Compound 72 is related to 71 with a methyl ester moiety instead of the carboxylic acid moiety at C-2 in 71. It was proposed that methyltransferase may be accountable for the C-1 carboxyl group methylation. It is noteworthy that 71 exhibited no inhibition on NO production boosted by LPS in the RAW 264.7 cells (Conc. 100 mM), however, its C-1 methyl ester 72 possessed (IC 50 18.6 mM) marked inhibitory potential, comparing to indomethacin (IC 50 37.5 mM), suggesting esterication enhanced the activity. 14 Whilst 123 and 125 were inactive in assays for both NF-kB inhibition and mitochondrial transmembrane potential. 19 New dimeric benzophenones; 137-139 and benzophenone monomers; 61, 63, and 64, along with 55 and 62 were isolated from Pleosporales sp. YY-4 associated with Uncaria rhynchophylla by SiO 2 /RP-18/HPLC and assigned by HREIMS and NMR. Compounds 137-139 are the rst C bridged benzophenone dimers. These metabolites were evaluated for their anti-inammatory activity by examining their inhibition of NO production induced by LPS in the RAW 264.7 cells using CCK-8 assay. Compounds 64 and 137-139 possessed more noticeable inhibition potential versus LPS-caused NO production in the RAW 264.7 cells (IC 50 ranged from 8.8 to 23.3 mM) than dexamethasone (IC 50 22.2 mM). The dimeric derivatives 137-139 were more potent than the monomers 61-63 and 55 that displayed moderate anti-inammation potential (IC 50 ranged from 35.1 to 43.3 mM). 63 3.8. a-Glucosidase, proteasome, and tyrosine phosphatase inhibitory activities a-Glucosidase catalyses the glycosidic bonds hydrolysis of nonreducing saccharide polymers to give glucose. 100 a-Glucosidase inhibition controls the postprandial blood level due to slowing the dietary carbohydrates uptake. 101,102 a-Glucosidase inhibitors have been assumed to be therapeutic agents for carbohydrate-related metabolic disorders such as diabetes.
The chemical investigation of the EtOAc extract of Aspergillus avipes PJ03-11 resulted in separation of a new benzophenone, 11, along with 12 and 21 by repeated SiO 2 /Sephadex LH-20 CC/ RP-HPLC. Compounds 12 and 21 (IC 50 s 0.199 and 0.042 mM, respectively) demonstrated stronger a-glucosidase inhibition potential than acarbose (IC 50 0.685 mM) and quercetin (IC 50 0.015 mM), while 11 (IC 50 > 2.0 mM) had modest activity. 38 Further, compound 52 was reported to exhibit powerful aglucosidase inhibition than acarbose. 58 KATP channel has a major function in the control of b-cell membrane potential. pancreatic b-cells KATP channel inhibitors help the release of insulin and are used as antidiabetics such as sulfonylureas, however, the usage of KATP channel blockers leads to a high incidence of hypoglycaemic events. 51 It was reported that voltage-gated K channels modulation could be an alternative in antidiabetic indications. b-cell Kv2.1 (voltage-dependent K + ) channel contributes to insulin-secreting cell repolarization and regulates pancreatic insulin secretion. 103 The b-cell Kv2.1 currents prohibition results in prolongation of the action potentials and sustaining voltage-dependent Ca 2+ channels opening, therefore enhanced glucose-boosted insulin release without producing risky hypoglycaemia. Therefore, the b-cell Kv2.1 channel is targeted for T2DM treatment. 51 Two new benzophenones, acredinones A (140) and B (141), along with 42 were separated from the marine spongeaccompanied Acremonium sp. EtOAc extract utilizing SiO 2 CC and RP-HPLC (Fig. 14). Their structures were elucidated by spectroscopic data and chemical derivatization. They were assayed for inhibition of the outward K + currents in INS-1. Compounds 140 and 141 revealed notable inhibitory potential on voltage-gated K + channel in INS-1 cells (IC 50 s 0.59 and 1.0 mM, respectively), while 42 had no inhibitory activity. 51 These metabolites represent the rst nonpeptidic natural metabolites, possessing marked outward K+ currents prohibition in INS-1 cells.

Anti-osteoclastogenic activity
Osteoclasts overactivity results in excessive bone resorption that breaks the bone resorbing/forming balance, leading to osteopenic disorders such as Paget's disease, periodontal disease, osteoporosis, and rheumatoid arthritis. 104 The RANK/RANKL signalling pathway activates substantial signalling molecules for osteoclast function and development. 105 Several reports investigated the inhibitory potential of natural metabolites on RANKL-mediated osteoclast differentiation aiming at discovering new drug leads for treating osteoporosis. 106 A new RANKL-induced osteoclast differentiation inhibitor, acredinone C (142), along with related analogs 140 and 141 were separated from Acremonium sp. F9A015 culture broth EtOAc extract utilizing RP-HPLC. Compound 142 incorporates xanthone and benzophenone moieties, that was established by NMR and MS analyses. These acredinones effectively prohibited the RANKL-produced formation of TRAP + -MNCs without any toxicity up to 10 mM. Their anti-osteoclastogenic potential was correlated with the downstream effectors' blockage via downregulating of NFATc1 (nuclear factor of activated-T cells, cytoplasmic 1) expression through inhibiting signalling molecules: ERK, p38, IkBa, and AKT. Further, 140 possessed dual potential on osteo-clasto-genesis and osteo-blasto-genesis, where its osteogenic potential was due to osteoblast-specic genes upregulation through BMP family members control and Smad signalling pathway. Additionally, 140 had marked boneformation potential in the in vivo mouse model, thence, 140 could be a potential lead as an anabolic agent and/or antiresorptive agent to prohibit and heal bone disorders. 87

Antihyperlipidemic activity
Body stores excessive energy as lipid droplets in adipocytes that act as an energy reservoir. Excessive storage of lipids was found to be a cause of diverse disorders, including cardiovascular disease, T2DM, and atherosclerosis. 107 Chemical examination Cinachyrella sp.-associated Emericella variecolor resulted in separation of a new metabolite; 19-Omethyl-22-methoxypre-shamixanthone (93), together with 94 using SiO 2 /RP-18/Sephadex LH-20 and semipreparative HPLC that were elucidated based on extensive spectroscopic, ECD, and Xray analysis as well as Mosher's method. These metabolites were examined for lipid-lowering potential on OA (oleic acid)-elicited lipid accumulation in the HepG2 cells by measuring Oil Red O staining. Compound 94 exerted marked lipid accumulation inhibition potential (Conc. 10 mM) comparable to that of simvastatin accompanied with potent reducing of intracellular TG (triglyceride) and TC (total cholesterol), without toxicity toward HepG2 cells up to 100 mM in the MTT assay. It mediated its lipid accumulation inhibitory potential through down-regulating the expression of the principal lipogenic transcriptional factor; SREBP-1c (sterol regulatory element-binding transcription factor 1) and its down-stream genes, including FAS (fatty acid synthase) and ACC (acetylCoA carboxylase). Thence, it lessened lipid accumulation via SREBP-1 pathway downregulation with no toxicity, suggesting its potential as lead compound for developing anti-hyperlipidemic agent. 73 3.11. Sterol O-acyltransferase inhibitory activity SOAT-2 (sterol O-acyltransferase-2) is belonging to the membrane-bind O-acyl-transferase family that adjusts the body metabolism of cholesterol. 70,108 It is principally expressed in the small intestine and hepatocytes. It has been reported as a substantial target for treating/preventing atherosclerosis and hypercholesterolemia than SOAT1. 70 A new indanone analog: celludinone B (143), along with 88 were puried from Talaromyces cellulolyticus BF-0307 culture broth by RP-18 CC and HPLC and assigned by NMR spectral data. Their SOAT (sterol O-acyltransferase) inhibition potential was assessed on SOAT-1(sterol O-acyltransferase-1) and SOAT-2 (sterol O-acyltransferase-2) isozymes in the cell-based assay using SOAT-1-and -2-CHO (Chinese hamster ovary) cells. Compounds 88 and 143 displayed noticeable SOAT-1 and SOAT-2 inhibitory capacity (IC 50 s 9.9 and 0.91 mM for 88 and 2.8 and supplemented fermentation media. Therefore, these techniques could be applied for discovering new lead metabolites.
These metabolites have been assessed for various bioactivities, the major metabolites ones were evaluated for antimicrobial and cytotoxicity. It is noteworthy that limited studies investigated the anti-inammation, anti-mycobacterial, antialgal, Plant growth inhibitory, anti-nematode, antioxidant, phytotoxic, insecticidal, antihyperlipidemic, antiosteoclastogenic, immune-suppressive, anticoccidial, and antimalarial, as well as a-glucosidase, proteasome, tyrosine phosphatase, protein kinase, and sterol O-acyltransferase inhibitory activities of these metabolites.
The reported structure-activity studies revealed that the substitution pattern of these class of metabolites was greatly inuenced various activities as summarized in Fig. 18.
It is noteworthy that limited studies exploring the mechanism of action of these metabolites were reported. For example, 140 had anabolic and/or anti-resorptive potential through osteoblast-specic genes up-regulation through BMP family members control and Smad signalling pathway that could prohibit and heal bone disorders. Compound 94 mediated antihyperlipidemic effect via SREBP-1 pathway downregulation. Compounds 146 and 147 possessed potent antimetastatic and antitumor through various mechanisms, suggesting their potential as promising new lead metabolite for nding out chemotherapeutic agents.
These metabolites worthy deserve further investigation as potential leads of therapeutic agents. The benzophenone dimerization via a S-ether functionality was greatly affected the activity, therefore, this could be a benecial approach of synthetic research to modulate the selectivity and bioactivity of these metabolites. Future studies on the structure-activity relations, molecular mechanisms, and in vivo investigations of these metabolites are highly recommended.
Lastly, fungal benzophenones have diverse and oen powerful bioactivities, and it is probable that more metabolites belonging to this class will be brought to light in the coming years. The creation of these metabolites through chemical synthesis could be an interesting area for future research by organic chemists.